This proposal represents a continuation of a long-term project with the development of a coherent understanding of the factors responsible for altering thyroid hormone production, metabolism, delivery and disposal in states of thyroid hormone deficiency and excess, systemic illnesses, fasting and undernutrition in man. Particular areas of investigation include: 1) The determination of the mechanisms responsible for maintaining triiodothyronine blood levels by altering peripheral tissue thyroxine to triiodothyronine conversion in states of thyroxine deficiency or excess. 2) Evaluation of the metabolic consequences of altered circulating thyroid hormone levels which occur with fasting and undernutrition. 3) Determination of the major tissues and organs which are responsible for the in vivo production of triiodothyronine and reverse triiodothyronine from thyroxine. 4) Investigation of the humoral signals which appear responsible for altering free thyroxine levels, the efficiency of conversion of thyroxine to triiodothyronine and the inhibition of pituitary TSH release in fasting and nonthyroidal illnesses. 5) Determination of the mechanisms responsible for producing nonthyroid hormone suppressible thyroxine secretion by the thyroid gland in normal subjects and possible alterations which may occur in patients with nontoxic goiter, thyroid glandular injury resulting from X-ray therapy, and in certain subjects with obesity. Although some animal studies are proposed in this grant, the principal focus will be on human subjects with the view that unique differences in the regulatory control mechanisms for thyroid hormone metabolism occur in man.